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Diet, Oxidative Stress, CR - Coggle Diagram
Diet, Oxidative Stress, CR
Oxidative Stress
- When cells use oxygen, they produce reactive oxygen species (ROS), potentially toxic.
- Particularly mitochondria release small amount superoxide anion O2- and peroxide O2-2.
- Imbalance b/w pro-oxidants and anti-oxidants leads to toxic accumulation ROSs
ROS
- What goes right. O2 + 4e- (electrons) + 4H :arrow_right: oxidative phosphorylation :arrow_right: 2H20.
- When goes wrong, oxygen takes one/two further electrons leading to anion or peroxide above. Very dangerous for physiology cells.
- ROS peroxide membranes modify DNA in many ways, deactivate enzymes, increase proteolysis breakdown proteins *(Sohal & Weindruch, 1996).
Antioxidants
- range of them inside cell that convert released ROS into safe molecules
- Super Oxide Dismutase (3 types), glutathione most important, but many others too
- SOD1 antioxidant is cytoplasmic form of SOD molecule which scavenges superoxide anions not already been scouted.
- Transgenic up-regulation SOD1 in mice appears to protect neurons (Cardozo-Pelaez et al., 1998)
- Also reduced neurodegeneration (Borg & Chereual, 2008)
- SOD1 overexpression prevents premature death in APP overexpressing transgenic mice, linking implications for AD (Borg & Chereul, 2008).
- Problems - voluntary wheel running voles (40% more energy expenditure) showed virtually no differences in anti-oxidant enzyme activities, nor oxidative damage. More energy output = more ROS, yet no evidence it makes any difference to anti-oxidants (Selman et al., 2002). Not yet understood
- Antioxidants seem to confer significant neuro-protective characteristics, have ability to halt age-related damage in the brain. BUT interaction with other factors e.g., exercise, poorly understood.
Normal Ageing
- 38% 60-78 year olds show -1SD memory performance in absence of pathology (Koivisto et al., 1995)
- Episodic, working, spatial and implicit memory all decline in normal ageing (Hedden & Gabrielli, 2004)
- Fine motor control compromised and motor tasks slow (Mattay et al., 2002)
Oxidative Damage
- Some evidence oxidative damage and reduction anti-oxidant function in areas associated with motor control (Substantia Nigra; Venkateshappa, 2011)
- Increased oxidative damage in ageing brain, SOD1 knockout mice reduced lifespan (Finkel & Holbrook, 2000) BUT no decrease lifespan for knockouts SOD2, glutathione, thioredoxin.
Synaptic Plasticity
- Synaptic Plasticity = ability synapses strengthen and weaken over time as function of increase/decrease in activity.
- Long-term potentiation key to memory formation. Process whereby after repeated stimulation, synapse responds at much greater rate than prior to repeated stimulation.
- Post-synaptic spines of hippocampal CA1 neurons have NMDA and AMPA glutamate receptors both permeable to NA+ and K+.
- NMDA **also permeable to Ca2+, but under most circumstances the Ca2+ channel is blocked by Mg2+**
- When glutamate binds to post-synaptic membrane, there is usually no influx Na+ or Ca2+ at NMDA receptor because it's blocked by Mg2+
- Weak stimulation does not activate the NMDA receptor, and the excitatory postsynaptic potential (EPSP) produced only by AMPA receptor
- High frequency stimulation results in spatial and temporal summation of the EPSPs, highly depolarising the post-synaptic membrane (inside cell becomes positive)
- Positively charged Mg2+ effluxes, and Ca2+ enters through NMDA receptor.
- Influx Ca2+ activates protein kinases CAMKII and PKAII which makes a cascade of molecular consequences
- CaMKII transports more AMPA receptors to synapse (Hayashi et al., 2000)
- PKAII increases dendritic spine volume and greater amount transmitter released from pre-synaptic neurons
- Ca2+ increases CREB (a cAMP response-element binding protein transcription factor that runs up into DNA for major growth hormone.. Response elements are DNA sequences include BDNF (synaptogenesis role) regulates diverse cellular responses, including proliferation, survival, and differentiation)
- Glutamate released after LTP opens greater number channels and produces larger EPSPs
- Influx Ca via NMDA receptors leads host of changes. Ca binds to proteins that cause increase AMPA receptors, and increases CREB which increases number synapses.
- Ca influx via NMDA :ARROW_RIGHT: increase CREB :ARROW_RIGHT: increase BDNF :arrow_right: increase no. synapses
Relation to Ageing
- Ageing correlated with reduction excitability hippocampal CA1 neurones and increase in magnitude and duration of afte-rhyperpolatisation phase (Langfield et al., 1984)
- Ageing neurones reduced Ca2+ entry via NMDA receptors and increased Ca2+ activating after-hyperpolarisation phase.
- These changes in Ca2+ dynamics reduce LTP and LTD in ageing neurones, and change in Ca2+ permeability now known associated with oxidative stress, and influenced by glutathione levels (Steullet et al., 2006)
- Damage resulting from oxidative stress/reduction in antioxidants (e.g., glutathione) function reduces long-term synaptic plasticity hippocampal neurones. Clear evidence age-related changes in neuronal function that mirrors normal age-related memory loss.
- BUT similar changes afterhyperpolarisation induced by changes in other markers such as corticosteroid and oestrogen levels (Kumar & Foster, 2007) and overexpression antioxidant genes have little correlation with cognitive performance even though reduce markers oxidative damage (Lee et al., 2011)
Conclusions
- Normal ageing relatively modest effects human cognitive performance
- Normal age-related memory loss appears due to changes Ca2+ dynamics, with evidence consistent with notion oxidative stress may underly memory losses
- But third, unknown, molecular player cannot be ruled out
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Diet
- Widespread evidence diet influences lifespan (Lagiou et al., 2006)
- Effects diet-related parameters implicated cognitive performance and AD
- Healthy diets tend to be associated with people who live longer. Longitudinal study 15 years analysed healthy, prudent and healthy diets (Osler et al., 2001)
Cholesterol
- Lesser et al. (2009) - 358 nursing home residents had serum lipids measured upon admission to home, and neuropathology evaluated at autopsy.
- Those w/ AD pathology had higher cholesterol and higher low-density lipoprotein ('bad' cholesterol)
Alcohol
- Sink et al. (2009) - 3000 subjects aged 75+ without dementia. Followed for 6 years, and self-reported alcohol intake.
- Moderate alcohol intake (1-2 per day) had 37% lower risk of dementia in those with normal cognition (not for mild cognitive impairments)
- Patients with MCI at baseline, any amount alcohol had faster cognitive decline
- High alcohol intake (more than 14/week) twice as likely to develop dementia compared to non-drinkers with mild cognitive impairments
Vitamin
- Gale et al. (1996) - cognitive impairment associated with lower vitamin C intake/plasma concentration in healthy elderly
- Goodwin et al. (1983) - same for memory and abstract thinking.
- BUT vitamin C ascorbate acts to prevent oxidation, so is antioxidant reduction due to pathology, or the other way around?
Obesity
- Pasinetti et al. (2014) - 9 week old mice exposed to high fat diet 15 weeks. Exhibited obesity and insulin resistance. Then returned to low-fat diet where exhibited normal body weight and glucose tolerance
- At 85 weeks, mice still showed severe deficits in learning and memory tasks. Post-mortem, they had reduced expression of BDNF and had synaptic impairments in hippocampus
Mediterranean Diet - High consumption fruit, berries, veg, beans, nuts, whole grains, olive oil, red wine, species. Low consumption saturated fat, dairy, red meat and poultry.
- Ageing - Longitudinal Study (Lagiou et al., 2006) - Med diet 42,000 young women (30-49) for 12 years. Found significant reductions in mortality (13%) and cancer mortality (16%). Appears to reduce mortality even in young people
- Alzheimer's - 1292 cognitively normal elders followed for 4.5 years. 275 developed MCI. Compared to the lowest diet adherence, middle had 45% lower risk AD, and highest 48% lower risk. (Scarmeas et al., 2009). Mechanism is unknown, as no evidence for anti-inflammatory or metabolic effects of the diet (Gu et al., 2010)
- Oxidative Stress - Med diet reduced plasma oxidative stress (glutathione) in 138 twin pairs and 21 unpaired twins, not confounded by genetics or shared environment. May increase protection against ROS. (Dai et al., 2008). 1-year Med diet intervention on plasma non-enzymatic antioxidant capacity 564 ps high cardiovascular risk. Found med diet increased plasma anti-oxidant levels subjects high risk cardiovascular disease (Zamora-Ros et al., 2013).
- MD typically attributed to antioxidant anti-inflammatory effects by to date no direct evidence for it
Ketogenic Diet - high fat, medium protein, low carb. Highly effective anti-convulsant regime for epilepsy treatment. Forces body burn fats rather than carbs. Liver converts fat into fatty acids and ketone bodies, ketones pass into brain and replace glucose as energy source, and blood sugar levels reduce and stabilise.
- Ageing - KD improves performance and object recognition in aged rats (Xu et al., 2010) and medium chain triglycerides (MCT) variant shown to increase mitochondrial density and function in aged rats (Ballietti et al., 2010).
- AD and Epilepsy - seizures more common in AD, particularly fAD (Amatniek et al., 2006), enhanced propensity seizures AD mice (Roberson et al., 2011). AD characterised by neuronal degeneration, recent evidence suggest neuronal excitability increases in AD (both biomarkers implicated in seizures and atypical neuron firing).
- KD and AD - Ketone bodies protect neurones against amyloid-beta toxicity (Kashhiwaya et al., 2000). Significant improvement cognitive function those without APOE4 variant, but not for those with the variant (Henderson et al., 2009)
- KD effects attributed to metabolic, vascular, antioxidative mechanisms due to ketone metabolism, but KD also increases two MCT fatty acids octanoic and decanoic acid, which show increase decanoic probably anti-convulsant played in KD, not ketone body. Decanoic acid directly blocks seizures by blocking post-synaptic ion channels. Specifically, it inhibits ionotropic glutamate receptor AMPA.
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SUMMARY
- Diet profoundly modulates neuropathology. ROS, vascular and metabolic mechanisms of action that are all richly intertwined.